Disorders of cognition are generally accompanied by symptoms of forgetfulness, confusion, memory loss, and other aspects as a result of aging, brain injury or disease. The concomitant decrease in cognitive function during the aging process has been documented in various mammals and more recently in human subjects as well. In particular, presenile and senile primary degenerative dementia appear to be common causes of mental deterioration among the elderly. In fact, the symptoms of cognitive disorder appear to be associated with decreased acetyl choline synthesis as well as impairment of the choline receptive neurons. Especially, the activity of the enzyme choline acetyl transferase (CAT) which catalyzes the synthesis of acetyl choline from its previous choline and acetyl coenzyme A can be severely reduced as reflected by the loss of cholinergic (acetyl choline releasing) nerve endings in the hippocampus. The cholinergic terminals are recognized as critically important to memory function.
The alkaloid arecoline, e.g. methyl 1-methyl-1,2,5,6-tetrahydropiperidine-3-carboxylate, derived from Areca catechu (betel nut) is a natural cholinergic agonist of short biological half-life with both central and peripheral muscarinic effects. Arecoline is however toxic in mammalian systems and limited to veterinary anthelmintic use.
O-substituted tetrahydropyridine ether oximes are alkaloid derivatives known to have pharmacological properties that make them useful as cholinergic agents. In particular, the preferred compound CI-979 is a newly discovered cognition activator as described in U.S. Pat. No. 4,786,648 to Bergmeier, et al, which disclosure is incorporated by reference in the present specification. Therefore, the drug CI-979 HCl has been under consideration for therapy of age-associated memory impairment and primary degenerative dementia. Furthermore, the cognition activator CI-979 HCl is being developed for the treatment of Alzheimer's disease.
Specifically, CI-979 has the following structural formula (Ia): ##STR1##
As can be seen in formula (Ia), CI-979 contains a methyloxime group attached to the basic tetrahydropyridine ring to form 1,2,5,6-tetrahydro-1-methyl-3-pyridine methyloxime. Similar to other pyridine derivatives, the free base form of CI-979 is a volatile oily liquid, whereas CI-979 monohydrochloride is obtained as a stable white crystalline salt.
In the course of preformulation studies, the storage stability of the drug has been tested by exposure to heat, UV light, and extremes of the pH range. Specifically, it has been found that the HCl salt is converted in the presence of basic or neutral excipients and even minute amounts of moisture to the volatile free base form that consequently evaporates. Furthermore, in acidic environments of less than about pH 5 the drug undergoes hydrolysis to an aldehyde degradation product of CI-979. See FIG. 1, compound (A). The acid hydrolyzed products of the drug CI-979 HCl are virtually devoid of biological activity.
As illustrated in FIG. 1, two major degradation pathways have been proposed for CI-979 HCl. One pathway represents the hydrolysis to the aldehyde compound (A), 1,2,5,6-tetrahydro-1-methyl-3-pyridine carboxaldehyde, under acidic (i.e. &lt;pH5) conditions.
The second pathway consists of isomerization to the syn- (or Z-) isomer of CI-979 by exposure to UV light.
In particular, hydrolysis of CI-979 to the aldehyde form is a temperature dependent first-order reaction. The light-catalyzed reaction of CI-979 HCl in solution is apparently somewhat pH-dependent, with the highest rate of isomerization occurring at about pH 8.0. The UV light energy presumably weakens the oxime double bond and potentiates rotation to a thermodynamically less stable state.
Moreover, the alkaloid drug, CI-979 HCl, has been found to be labile in acidic and neutral, even in the solid state with only slightly humid microenvironments, microenvironment being defined as the ambient conditions surrounding a given molecular aggregate or agglomerate. In fact, CI-979 HCl undergoes hydrolysis as a solid mixture formulated in bulk with polyhydroxy excipients. However, only minimal isomerization has been observed as measured by reverse phase high performance liquid chromatography.
Consequently, the storage stability problem of the drug as a solid formulation represented a two-fold dilemma. On the one hand, an acid microenvironment would cause hydrolysis of CI-979 HCl, although preventing conversion of the HCl-salt to the free base and subsequent volatilization. On the other hand, a neutral or alkaline microenvironment would diminish CI-979 degradation but allow formation of the volatile free base of the drug.
Plant derived polysaccharides such as starch are used by the skilled in the art as diluent, binder or disintegrant material in solid dosage forms. U.S. Pat. No. 4,812,445 discloses a process for encapsulating materials in the matrix of aqueous starch slurries. U.S. Pat. No. 4,786,648 discloses the use of polysaccharides such as dextrose and starch as carrier or binder material in tablets and powders. U.S. Pat. No. 3,523,871 reports a process for stabilizing the enzyme catalase by the use of soluble starch (inter alia) in order to obtain a stable, homogeneous and non-hygroscopic preparation.
Notwithstanding the well-known uses of starch and similar neutral polysaccharides in pharmaceutical preparations, stabilization for improved shelf life of the subject oximes having the aforedescribed two-fold lability has remained a problem.
It is therefore the object of the present invention to provide a solid composition for stabilizing certain alkaloid methyloximes, such as the cognition activating agent, CI-979 HCl for use in the treatment cognitive disorders. In particular, it is the object of the present invention to provide triturate of the drug in a solid neutral excipient such as starch which simultaneously avoids hydrolytic degradation and neutral/base volatilization of the alkaloid drug.
It is the further object of the present invention to provide a method of preparing a solid starch composition stabilizing the cholinergic alkaloid methyloximes such as the cognition activator, CI-979 HCl.